Ly-2+ T cells cultured at limiting dilution with concanavalin A and irradiated spleen filler cells develop into clones of Ly-2+ cytotoxic T lymphocytes (CTL), which although initially specific, lyse a wide range of target cells by days 8 to 9. This anomalous nonspecific killing is now shown to be a function of the largest cells within the clone, with the majority of CTL behaving normally. Cold-target inhibition experiments demonstrate that two distinct recognition systems determine the broad-range killing, one being typified by a high affinity for P815 tumor cells, the other being typified by an affinity for YAC-1 tumor cells. Mouse strains differ in the probability that CTL in culture will demonstrate one or another of these killing patterns; some develop both, some one, and some neither. When both killing patterns develop, as in cultures of Ly-2+ cells from CBA mice, both are expressed in the same clone. High natural killer (NK) cell strains are those most likely to develop CTL clones with an ability to lyse the NK target YAC-1. The results have implications for the relationship of NK cells to T cells. They also suggest ways of avoiding the problem of anomalous T cell killing.